Recurrent KAT6B/A::KANSL1 Fusions Characterize a Potentially Aggressive Uterine Sarcoma Morphologically Overlapping With Low-grade Endometrial Stromal Sarcoma

Abstract

With the widespread application of next-generation sequencing, the genetic landscape of uterine mesenchymal neoplasms has been evolving rapidly to include several recently identified fusion genes. Although chromosomal rearrangements involving the 10q22 and 17q21.31 loci have been reported in occasional uterine leiomyomas decades ago, the corresponding KAT6B::KANSL1 fusion has been only recently identified in 2 uterine tumors diagnosed as leiomyoma and leiomyosarcoma. We herein describe 13 uterine stromal neoplasms carrying a KAT6B::KANSL1 (n=11) and KAT6A::KANSL1 (n=2) fusion. Patient ages ranged from 33 to 81 years (median, 49 y). Tumor size was 2.6 to 23.5 cm (median, 8.2 cm). Nine tumors were myometrium-centered, and 3 had an intracavitary component. Original diagnoses were mostly low-grade endometrial stromal sarcoma (LG-ESS; 10 cases) with atypical features (limited CD10 expression, sex cord-like features, pericytic vasculature, and frequent myxoid changes). Treatment was hysterectomy±bilateral salpingo-oophorectomy (10), myomectomy (1), and curettage (2). Five patients were disease-free at 6 to 34 months, 3 (27%) died of disease at 2 to 47 months, and 3 were alive with disease at 2, 17, and 17 years. Histologically, most tumors showed variable overlap with LG-ESS, but they were generally well-circumscribed lacking the extensive permeative and angioinvasive growth typical of LG-ESS. They were composed of monotonous medium-sized oval and spindle cells arranged into diffuse sheets with prominent spiral-type arterioles and frequent pericytoma-like vascular pattern. Variable myxoid stromal changes were frequent. Mitotic activity ranged from 1 to >20 in 10 HPFs. Immunohistochemistry showed variable expression of CD10 (12/13), estrogen receptor (8/11), progesterone receptor (8/11), smooth muscle actin (9/11), desmin (4/12), h-caldesmon (2/10), calretinin (3/8), inhibin (1/7), WT1 (4/7), cyclin D1 (5/11; diffuse in only 1 case), and pankeratin (5/10). This series characterizes a KAT6B/A::KANSL1 fusion-positive uterine stromal neoplasm within the morphologic spectrum of LG-ESS but with atypical features. The relationship of these neoplasms to genuine LG-ESS remains unclear. This molecular subtype of uterine endometrial stromal sarcoma has the potential for an unfavorable clinical course despite the absence of widely invasive growth; nevertheless, analysis of more cases is necessary to delineate the phenotypic spectrum and biological potential of this tumor.

FIGURE 1

Representative examples of the gross and low-power features of KAT6B::KANSL1 fusion sarcomas. A: Gross image showing homogeneously tan-colored well-circumscribed nodule with subtle peripheral lobulation confined to the myometrium. B: Low power of same case highlights well-defined non-infiltrative borders at the myometrial interphase. C: This case showed myoinvasive borders akin to conventional LG-ESS. D: Tongue-like vascular permeation in same case.

FIGURE 2

Examples of the common histological features of KAT6B::KANSL1 fusion sarcomas. A: LG-ESS-like pattern with prominent spiral-type arterioles is seen in particular near the myometrium. B: Cellular areas with ovoid to spindled cells, note necrosis (upper left field). C: Brisk mitotic activity is seen also in the low-grade looking areas in mitotically highly active tumors (arrow heads). D: Fibrosarcoma-like spindle cell pattern with brisk mitotic activity (arrow heads).

FIGURE 3

Representative images of the myxoid feature in KAT6B::KANSL1 fusion sarcomas. A: Abrupt transition from moderately pink (myoid) areas to myxoid area. Note gradual merging of the myoid area (midfield) and more dark-stained areas (lower right). B: Focal epithelioid areas showing abrupt transition to arteriole-rich paucicellular myxoid area. C: Higher magnification of fibromyxoid spindled areas showing prominent vascularization. D: Prominent pericytoma-like vascular pattern.

FIGURE 4

Examples, of unusual features in KAT6B::KANSL1 fusion sarcomas. A+B: Prominent sex cord-like pattern (note transition to striking myoid features in A upper right field). C: Small focus of hyaline collagenous spherules entrapping rounded primitive cells amid highly cellular sarcomatous background. D: Brightly eosinophilic collagen fibers as major stromal component are seen focally. E: This single example of sarcomatous highly pleomorphic tumor shows transition from spindled fascicular growth to undifferentiated epithelioid small round cell morphology. F: This case shows alternating fascicles of dark-stained smaller cells and moderately eosinophilic (myoid) spindled cells.

FIGURE 5

Representative images of the immunohistochemical findings in KAT6B::KANSL1 fusion sarcomas. A: Variable CD10 expression is noted. B: Strong and diffuse CD10 expression is seen in this case with sex cord like features. C: Homogenous expression of estrogen receptor. D: Moderate cytoplasmic expression of smooth muscle actin is seen in this case with KAT6A::KANSL1 fusion.

FIGURE 6

Integrated Genome Viewer (IGV) split-screen view of read alignments of the identified KAT6A::KANSL1 (upper picture; Case 2) and KAT6B::KANSL1 (lower picture; Case 3) fusion event. Shown are the breakpoints in the KAT6A and KAT6B locus (left) and the KANSL1 locus (right), respectively. Alignments whose mate pairs are mapped to the fusion sequence are multi-colored (soft clips).

FIGURE 7

Representative images of fluorescence in situ hybridization (FISH) in Case 1 showing break-apart signals (indicated by arrowheads) in both KAT6B (A) and KANSL1 (B). Red, centromeric; green, telomeric. C: RT-PCR confirming KAT6B::KANSL1 fusion in Case 10.